High Isoniazid Exposures When Administered with Rifapentine Once Weekly for Latent Tuberculosis in Individuals with Human Immunodeficiency Virus

Abstract

Isoniazid pharmacokinetics are not yet well-described during once weekly, high-dose administrations with rifapentine (3HP) for latent tuberculosis infection (LTBI). Fewer data describe 3HP with dolutegravir-based antiretroviral therapy for the treatment of human immunodeficiency virus (HIV). The only prior report of 3HP with dolutegravir reported elevated isoniazid exposures. We measured the plasma isoniazid levels in 30 adults receiving 3HP and dolutegravir for the treatment of LTBI and HIV. The patients were genotyped to determine NAT2 acetylator status, and a population PK model was estimated by nonlinear mixed-effects modeling. The results were compared to previously reported data describing 3HP with dolutegravir, 3HP alone, and isoniazid with neither dolutegravir nor rifapentine. The isoniazid concentrations were adequately described by a one compartment model with a transit compartment absorption process. The isoniazid clearance for slow (8.33 L/h) and intermediate (12 L/h) acetylators were similar to previously reported values. Rapid acetylators (N = 4) had clearance similar to those of intermediate acetylators and much slower than typically reported, but the small sample size was limiting. The absorption rate was lower than usual, likely due to the coadministration with food, and it was faster among individuals with a low body weight. Low-body weight participants were also observed to have greater oral bioavailability. The isoniazid exposures were consistent with, or greater than, the previously reported "elevated" concentrations among individuals receiving 3HP and dolutegravir. The concentrations were substantially greater than those presented in previous reports among individuals receiving 3HP or isoniazid without rifapentine or dolutegravir. We discuss the implications of these findings and the possibility of a drug-drug interaction that is mediated by cellular transport. (This study has been registered at ClinicalTrials.gov under identifier NCT03435146 and has South African National Clinical Trial Registration no. DOH-27-1217-5770.).

Keywords: 3HP; HIV; N-acetyltransferase 2; dolutegravir; isoniazid; latent tuberculosis infection; pharmacokinetics; rifapentine.

FIG 1

Visual predictive checks (VPC) and distribution of normalized prediction distribution errors on observations with simulation (NPDEYS) residuals for the final pharmacokinetic model, based on 1,000 simulated data sets from each model. The VPC solid lines indicate the median observed values, whereas the dashed lines indicate the 5th and 95th percentiles. The areas shaded in gray and purple show the ranges of values associated with the medians and the 5th and 95th percentiles in the simulated data sets. The NPDEYS residuals show associations between simulation-based residuals and predicted values, time, total body weight, and NAT2 acetylator type.

FIG 2

Pharmacokinetic summary statistics for N = 30 subjects enrolled in DOLPHIN, stratified by NAT2 acetylator status. The estimates are based on individual-level predictions from the final population pharmacokinetic model. AUC_0–24, area under the individually predicted concentration time curve from 0 to 24 h; C_max, maximum concentration; T_max, time of maximum concentration (hours).

FIG 3

(A) Comparison of observed isoniazid (INH) concentrations to DOLPHIN model predictions for three individuals reported by Brooks et al. (2018) (7) as receiving 3HP plus 50 mg dolutegravir daily. Solid points display the reported data values. Solid and dotted lines represent the 50th and 5th/95th percentiles, respectively, of 1,000 model-simulated concentrations. The AUC_0–24 and C_max estimates were reported by Brooks et al. (7). (B) Comparison of the 6 h INH concentrations reported by Lee et al. (2019) (15) among individuals receiving 3HP without dolutegravir. The mean (SD) body weight-adjusted (mg/kg) dose among N = 84 individuals reported by Lee et al. (15) was 14.0 (2.2) mg/kg, compared to 12.84 ± 2.3 mg/kg among the N = 30 participants in DOLPHIN. The NAT2 acetylator status was not reported by Lee et al. (15). SA, slow acetylator; IA, intermediate acetylator; RA, rapid acetylator.

FIG 4

Comparison of the dose-adjusted and weight-adjusted estimates of AUC_0–24 and C_extmax between DOLPHIN and a meta-analysis by Hong et al. (2020) (8). The estimates are stratified by NAT2 acetylator type for both studies and disease status for Hong et al. (8). SA, slow acetylator; IA, intermediate acetylator; RA, rapid acetylator; HV, healthy volunteers.